This Program Project is a collaborative effort by our University's Arteriosclerosis Research Center, Center for Prevention Research and Biometry, Comparative Medicine Clinical Research Center, and the Department of Obstetrics and Gynecology. In this Program Project we have addressed the primary prevention of two major public health problems of our country's women: coronary heart disease and osteoporosis. The rationale of this Program Project is based on the fact that women, like female cynomolgus macaques, experience premenopausal ovarian dysfunction, which sets the stage for the accelerated progression of both coronary artery atherosclerosis and osteoporosis postmenopausally. In Project 1 the objectives are to determine if, and to what extent, premenopausal treatment with a contraceptive steroid influences the progression of coronary artery atherosclerosis and osteoporosis postmenopausally among subjects with and without estrogen replacement therapy. Those questions are addressed as a part of a randomized, controlled, primary prevention trial using cynomolgus monkeys (Macaca fascicularis). A major part of the Program Project, in addition to the trial, are studies to explore the metabolic, cellular (Project 2) and psychophysiological (Project 3) mechanisms by which estrogens and progestins affect coronary artery atherosclerosis. The emphasis in Project 2 is on the effects of estrogen and progestins on lipoprotein distribution, composition and heterogeneity; the function capacity of HDL particles, arterial LDL uptake/degradation, endothelial cell turnover and the elaboration of certain cytokines and growth factors by macrophages and smooth muscle cells. The emphasis in Project 3 is on the effect of estrogen and progestins on cardiac responsivity to behavioral challenge and the neuroendocrine modulators of this responsivity. The results of this Program Project will provide an important comparative (nonhuman primate) basis for understanding better approaches to the prevention of coronary artery atherosclerosis and osteoporosis among middle-aged and older women.